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The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.
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; Pulit, Sara L 1
; Dekker, Annelot M 1 ; Ahmad Al Khleifat 2 ; Brands, William J 1 ; Iacoangeli, Alfredo 3 ; Kenna, Kevin P 4 ; Kavak, Ersen 5 ; Kooyman, Maarten 6 ; McLaughlin, Russell L 7 ; Middelkoop, Bas 1 ; Moisse, Matthieu 8 ; Schellevis, Raymond D 1 ; Shatunov, Aleksey 2 ; Sproviero, William 2 ; Tazelaar, Gijs H P 1 ; Rick A A Van der Spek 1 ; Perry T C Van Doormaal 1 ; Van Eijk, Kristel R 1 ; Joke Van Vugt 1 ; Basak, A Nazli 9 ; Blair, Ian P 10 ; Glass, Jonathan D 11 ; Hardiman, Orla 12 ; Hide, Winston 13 ; Landers, John E 4 ; Mora, Jesus S 14 ; Morrison, Karen E 15 ; Newhouse, Stephen 16 ; Robberecht, Wim 17 ; Shaw, Christopher E 2 ; Shaw, Pamela J 18 ; Philip Van Damme 17 ; Van Es, Michael A 1 ; Wray, Naomi R 19 ; Al-Chalabi, Ammar 2 ; Leonard H Van den Berg 1 ; Veldink, Jan H 1 1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
2 Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
3 Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, UK
4 Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
5 Genomize Inc. Bogazici University, Technology Transfer Region, ETAB, Istanbul, Turkey
6 SURFsara, Amsterdam, The Netherlands
7 Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
8 Department of Neurosciences, KU Leuven - University of Leuven, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium
9 Neurodegeneration Research Laboratory, Bogazici University, Istanbul, Turkey
10 Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
11 Department Neurology, Emory University School of Medicine, Atlanta, GA, USA; Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA
12 Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland
13 Biostatistics Department, Harvard School of Public Health, Boston, MA, USA; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
14 Department of Neurology, Hospital San Rafael, Madrid, Spain
15 Faculty of Medicine, University of Southampton, Southampton, UK
16 Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK
17 VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium
18 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
19 Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia